Identification of a Quantitative Trait Locus on Rat Chromosome 4 That is Strongly Linked to Femoral Neck Structure and Strength

Risk factors for osteoporotic hip fracture include reduced bone mineral density and poor structure of the femoral neck, both of which are heritable traits. Previously, we showed that despite similar body size, Fischer 344 (F344) rats have significantly different skeletal traits compared with Lewis (LEW) rats. To identify a gene or genes regulating fracture risk at the femoral neck, we mapped quantitative trait loci (QTL) for femoral neck density and structure phenotypes using a 595 F2 progeny derived from the inbred F344 and LEW strains of rats. Femoral neck phenotypes included volumetric bone mineral density (vBMD), neck width, femoral neck cross-sectional area and polar moment of inertia (Ip). A 20-cM genome-wide scan was performed using 118 microsatellite markers and linkage analysis was conducted to identify chromosomal regions harbor QTL for femoral neck phenotypes. Strong evidence of linkage (P<0.01) to femoral neck vBMD was observed on chromosomes (Chrs) 1, 2, 4, 5, 7, 10 and 15. QTL affecting femoral neck structure and biomechanical properties were detected only on Chr 4 where the F344 alleles were shown to improve femoral neck structure, whereas these alleles had no effect on bone measurements at the lumbar spine and only modest effects at the femoral midshaft. In contrast, QTL on Chrs 1, 2 and 10 affected multiple skeletal sites. Several QTL regions in this study are homologous to human chromosomal regions, where linkage to femoral neck and related phenotypes has been reported previously. These findings represent an important first step in localizing and identifying genes that influence hip fragility.